Benchtop 19F NMR Spectroscopy optimized Knorr pyrazole synthesis of Celecoxib and Mavacoxib, 3-(trifluoromethyl) pyrazolyl benzenesulfonamides Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Fluorinated organic compounds have demonstrated remarkable utility in medicinal chemistry due to their enhanced metabolic stability and potent therapeutic efficacy. Several examples exist of fluorinated non-steroidal anti-inflammatory drugs (NSAIDs) including diflunisal, flurbiprofen, and trifluoromethylated pyrazoles celecoxib and mavacoxib. These trifluoromethylated pyrazoles, which are most commonly constructed through cyclocondensation of a trifluorinated 1,3-dicarbonyl and an aryl hydrazine, are also found in numerous other drug candidates. Here, we interrogate the effects of solvent and the presence of Brønsted or Lewis acid catalysts on catalyzing this process. We highlight the utility of benchtop 19F NMR spectroscopy in enabling real-time quantification of reaction progress and identification of fluorinated species present in crude reaction mixtures without the need for cost-prohibitive deuterated solvents. Ultimately, we find that the reaction solvent has the greatest impact on rate and product yield, and also found that the relationship between keto-enol equilibrium of the dicarbonyl starting material pyrazole formation rate is highly solvent dependent. More broadly, we describe the optimization of the yield and kinetics of trifluoromethylpyrazole formation in the synthesis of celecoxib and mavacoxib, which is made possible through high-throughput reaction screening on benchtop NMR.